TY - JOUR
T1 - Identification of downstream genetic pathways of Tbx1 in the second heart field
AU - Liao, Jun
AU - Aggarwal, Vimla S.
AU - Nowotschin, Sonja
AU - Bondarev, Alexei
AU - Lipner, Shari
AU - Morrow, Bernice E.
N1 - Funding Information:
We thank Dr Radma Mahmood, Dr Xin Zheng, Mr David Reynolds, Mr Wen Tran, and Ms Shaoqing Yu for technical assistance; Dr. Mark Lewandoski for T-Cre transgenic mouse strain; Dr Marina Campione for ISH probes. We also thank Dr Jonathan Epstein, Dr Arthur Skoultchi, and Dr Evan Braunstein for critical reading and helpful comments on the manuscript. This work was supported by grants from NIDCD (R01DC05186-03) and the March of Dimes (FY2005-443) (B.E.M.).
PY - 2008/4/15
Y1 - 2008/4/15
N2 - Tbx1, a T-box transcription factor, and an important gene for velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) in humans, causes outflow tract (OFT) heart defects when inactivated in the mouse. Tbx1 is expressed in the second heart field (SHF) and is required in this tissue for OFT development. To identify Tbx1 regulated genetic pathways in the SHF, we performed gene expression profiling of the caudal pharyngeal region in Tbx1-/- and wild type embryos. Isl1, a key marker for the SHF, as well as Hod and Nkx2-6, were downregulated in Tbx1-/- mutants, while genes required for cardiac morphogenesis, such as Raldh2, Gata4, and Tbx5, as well as a subset of muscle contractile genes, signifying myocardial differentiation, were ectopically expressed. Pan-mesodermal ablation of Tbx1 resulted in similar gene expression changes, suggesting cell-autonomous roles of Tbx1 in regulating these genes. Opposite expression changes concomitant with SHF-derived cardiac defects occurred in TBX1 gain-of-function mutants, indicating that appropriate levels of Tbx1 are required for heart development. When taken together, our studies show that Tbx1 acts upstream in a genetic network that positively regulates SHF cell proliferation and negatively regulates differentiation, cell-autonomously in the caudal pharyngeal region.
AB - Tbx1, a T-box transcription factor, and an important gene for velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) in humans, causes outflow tract (OFT) heart defects when inactivated in the mouse. Tbx1 is expressed in the second heart field (SHF) and is required in this tissue for OFT development. To identify Tbx1 regulated genetic pathways in the SHF, we performed gene expression profiling of the caudal pharyngeal region in Tbx1-/- and wild type embryos. Isl1, a key marker for the SHF, as well as Hod and Nkx2-6, were downregulated in Tbx1-/- mutants, while genes required for cardiac morphogenesis, such as Raldh2, Gata4, and Tbx5, as well as a subset of muscle contractile genes, signifying myocardial differentiation, were ectopically expressed. Pan-mesodermal ablation of Tbx1 resulted in similar gene expression changes, suggesting cell-autonomous roles of Tbx1 in regulating these genes. Opposite expression changes concomitant with SHF-derived cardiac defects occurred in TBX1 gain-of-function mutants, indicating that appropriate levels of Tbx1 are required for heart development. When taken together, our studies show that Tbx1 acts upstream in a genetic network that positively regulates SHF cell proliferation and negatively regulates differentiation, cell-autonomously in the caudal pharyngeal region.
KW - Gene expression profiling
KW - Second heart field
KW - Tbx1
KW - VCFS/DGS
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U2 - 10.1016/j.ydbio.2008.01.037
DO - 10.1016/j.ydbio.2008.01.037
M3 - Article
C2 - 18328475
AN - SCOPUS:41149107746
SN - 0012-1606
VL - 316
SP - 524
EP - 537
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -